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Titolo:
DISCOVERY OF PROTOTYPE PEPTIDOMIMETIC AGONISTS AT THE HUMAN MELANOCORTIN RECEPTORS MC1R AND MC4R
Autore:
HASKELLLUEVANO C; HENDRATA S; NORTH C; SAWYER TK; HADLEY ME; HRUBY VJ; DICKINSON C; GANTZ I;
Indirizzi:
UNIV ARIZONA,DEPT CHEM TUCSON AZ 85721 UNIV ARIZONA,DEPT CHEM TUCSON AZ 85721 UNIV ARIZONA,DEPT CELL BIOL & ANAT TUCSON AZ 85721 UNIV MICHIGAN,MED CTR,DEPT INTERNAL MED ANN ARBOR MI 48109 UNIV MICHIGAN,MED CTR,DEPT PEDIAT ANN ARBOR MI 48109 UNIV MICHIGAN,MED CTR,DEPT SURG ANN ARBOR MI 48109 WARNER LAMBERT PARKE DAVIS,PARKE DAVIS PHARMACEUT RES,DEPT CHEM ANN ARBOR MI 48105
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 14, volume: 40, anno: 1997,
pagine: 2133 - 2139
SICI:
0022-2623(1997)40:14<2133:DOPPAA>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
MELANOCYTE-STIMULATING-HORMONE; MINIMAL ACTIVE SEQUENCE; ALPHA-MELANOTROPIN; MOLECULAR-CLONING; SKIN BIOASSAY; ANTAGONIST; EXPRESSION; PROTEIN; ANALOGS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
33
Recensione:
Indirizzi per estratti:
Citazione:
C. Haskellluevano et al., "DISCOVERY OF PROTOTYPE PEPTIDOMIMETIC AGONISTS AT THE HUMAN MELANOCORTIN RECEPTORS MC1R AND MC4R", Journal of medicinal chemistry, 40(14), 1997, pp. 2133-2139

Abstract

[Nle(4),DPhe(7)]-alpha-MSH (NDP-MSH), a highly potent analogue of alpha-melanocyte-stimulating hormone (alpha-MSH), possesses nanomolar efficacies at all the melanocortin receptor subtypes except the MCBR. Evaluation of the melanocortin ''message'' sequence of [Nle(4),DPhe(7)]-alpha-MSH was performed on the human melanocortin receptor subtypes designated hMC1, hMC3R, hMC4R, and hMC5R. Tetrapeptides and tripeptides were stereochemically modified to explore topochemical preferences at these receptors and to identify lead peptides possessing agonist activity and subtype selectivity. Four peptides were discovered to only bindto the hMC1 and hMC4 receptor subtypes. The tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 (I) possessed 0.6 mu M binding affinity at the hMC1R, 1.2 mu M binding affinity at the hMC4R, and agonist activity at both receptors. The tripeptides Ac-DPhe-Arg-Trp-MH2 (6) and Ac-DPhe-Arg-DTrp-NH2(7) possessed 2.0 and 9.1 mu M binding affinities, respectively, onlyat the hMC4R, and both compounds effected agonist activity. The tetrapeptide Ac-His-Phe-Arg-DTrp-NH2 (4) possessed 6.3 mu M affinity and full agonist activity at the hMC1R, while only binding 7% at the hMC3R, 36% at the hMC4R, and 11% at the hMC5R at a maximal concentration of 10 mu M These data demonstrate that the His-Phe-Arg-Trp message sequence of the melanocortin peptides does not bind and stimulate each melanocortin receptor in a similar fashion, as previously hypothesized. Additionally, this study identified the simplest structural agonists for the hMC1R and hMC4R receptors reported to date.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/09/20 alle ore 22:00:53